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Purpose To investigate high-energy phosphate metabolism in striated skeletal muscle of patients with Maternally Inherited Diabetes and Deafness (MIDD) syndrome. Materials and Methods In 11 patients with the MIDD mutation (six with diabetes mellitus [DM] and five non-DM) and eight healthy subjects, phosphocreatine (PCr) and inorganic phosphate (Pi) in the vastus medialis muscle was measured immediately after exercise using 31P-magnetic resonance spectroscopy (MRS). The half-time of recovery (t1/2) of monoexponentially fitted (PCr+Pi)/PCr was calculated from spectra obtained every 4 seconds after cessation of exercise. A multiple linear regression model was used for statistical analysis. Results Patients with the MIDD mutation showed a significantly prolonged t1/2 (PCr+Pi)/PCr after exercise as compared to controls (13.6±3.0 vs. 8.7±1.3 sec, P = 0.01). No association between the presence of DM and t1/2 (PCr + Pi)/PCr was found (P = 0.382). Conclusion MIDD patients showed impaired mitochondrial oxidative phosphorylation in skeletal muscle shortly after exercise, irrespective of the presence of DM. J. Magn. Reson. Imaging 2009;29:127–131. © 2008 Wiley-Liss, Inc.

Long-term follow-up study on bone mineral density and fractures after simultaneous pancreas-kidney transplantation. Background In type 1 diabetic patients with end-stage renal failure, low bone mass is prevalent and the incidence of fractures high after simultaneous pancreas kidney transplantation (SPK). Data are scarce on preexisting skeletal morbidity or the long-term effects of SPK on bone mass and risk of fractures. Methods We conducted a prospective study addressing these issues in 19 consecutive SPK recipients before and at 3, 6, and 12 months, and 2.5 to 4 years after establishment of graft function. Results Prior to transplantation, 13 patients (68%) had hyperparathyroidism, 7 of whom had osteoporosis. Mean bone mineral density (BMD) was significantly lower at the femoral neck than at the lumbar spine (T-scores -2.0 ± 0.89 vs. -0.66 ± 0.84). There was a significant decrease in BMD at both lumbar spine and femoral neck at 6 months post-transplantation (-6.0 ± 5.4% and -6.9 ± 4.3%, respectively). No further loss was observed in the following 6 months. At 1 year post-transplantation, 9 patients had osteoporosis associated with hyperparathyroidism in 8, and none had sustained a clinical fracture. A significant albeit small increase in BMD was observed 6 months after start of alfacalcidol 0.25 μg/day. At end-evaluation, osteoporosis and hyperparathyroidism persisted in the patients in whom it was documented at 1 year. Five patients who had lower BMD at the femoral neck pretransplantation sustained a clinical fracture. Conclusion Cortical osteoporosis is prevalent in SPK recipients at the time of transplantation, progresses early post-transplantation, and is associated with relatively high incidence of fractures. Reversal of persistent hyperparathyroidism with the use of alfacalcidol may contribute to a decrease in skeletal morbidity.

Diabetes mellitus is a chronic disease often leading to disabling microvascular and macrovascular complications. Intensive treatment with insulin can only delay the progression of these complications. Normalization of the glucose homeostasis will reduce the cardiovascular morbidity and mortality. At this time, whole-pancreas transplantation is the only option to achieve long-term insulin independence, resulting in an improvement or stabilization of the microvascular and, at least partly, the macrovascular lesions. Therefore, simultaneous kidney-pancreas transplantation has become the preferred treatment option for selected patients with type I diabetes mellitus and approaching end-stage renal disease. With the improving results of isolated pancreas transplantation, this procedure may be offered with increasing frequency to diabetics with a good functioning kidney transplant or to diabetics with overt diabetic nephropathy but preserved renal function. In this review we describe recipient and donor selection criteria, some surgical techniques, survival rates, and the currently used immunosuppressive protocols, and at the end we propose a treatment strategy.

Mutations in mitochondrial DNA (mtDNA) associate with various disease states. A few mtDNA mutations strongly associate with diabetes, with the most common mutation being the A3243G mutation in the mitochondrial DNA-encoded tRNA(Leu,UUR) gene. This article describes clinical characteristics of mitochondrial diabetes and its molecular diagnosis. Furthermore, it outlines recent developments in the pathophysiological and molecular mechanisms leading to a diabetic state. A gradual development of pancreatic β-cell dysfunction upon aging, rather than insulin resistance, is the main mechanism in developing glucose intolerance. Carriers of the A3243G mutation show during a hyperglycemic clamp at 10 mmol/l glucose a marked reduction in first- and second-phase insulin secretion compared with noncarriers. The molecular mechanism by which the A3243G mutation affects insulin secretion may involve an attenuation of cytosolic ADP/ATP levels leading to a resetting of the glucose sensor in the pancreatic β-cell, such as in maturity-onset diabetes of the young (MODY)-2 patients with mutations in glucokinase. Unlike in MODY2, which is a nonprogressive form of diabetes, mitochondrial diabetes does show a pronounced age-dependent deterioration of pancreatic function indicating involvement of additional processes. Furthermore, one would expect that all mtDNA mutations that affect ATP synthesis lead to diabetes. This is in contrast to clinical observations. The origin of the age-dependent deterioration of pancreatic function in carriers of the A3243G mutation and the contribution of ATP and other mitochondrion-derived factors such as reactive oxygen species to the development of diabetes is discussed.

OBJECTIVE—Mortality in type 1 diabetic patients with end-stage renal failure is high and dominated by coronary atherosclerotic events. With regard to prognosis, simultaneous transplantation of pancreas and kidney (SPK) may be superior to kidney transplantation alone (KTA) in type 1 diabetic patients, because normalization of blood glucose levels may reduce progression of coronary atherosclerosis and because it is well known that progression of coronary atherosclerosis is one of the major factors that determines clinical prognosis. However, no data are available on progression of coronary atherosclerosis after SPK. RESEARCH DESIGN AND METHODS—We performed an observational angiographic study comparing progression of coronary atherosclerosis, analyzed with quantitative coronary angiography, in patients with (n = 26) and those without (n = 6) a functioning pancreas graft after SPK, to test the hypothesis that normalization of blood glucose levels by SPK may indeed reduce progression of coronary atherosclerosis in type 1 diabetic patients and thereby improve prognosis. RESULTS—Mean follow-up was 3.9 years. Average glucose control was significantly worse for the patients without a pancreas graft than for patients with a functioning pancreas graft: 11.3 (SD 3.5) vs. 5.9 mmol/l (SD 1.1) (P = 0.03). Mean segment diameter loss (progression of diffuse coronary atherosclerosis) was 0.024 mm/year (SD 0.067) in patients with a functioning pancreas graft, compared with 0.044 mm/year (SD 0.038) in patients in whom the pancreas graft was lost. Minimum obstruction diameter loss (progression of focal coronary atherosclerosis) was 0.037 mm/year (SD 0.086) in patients with a functioning pancreas graft compared with 0.061 mm/year (SD 0.038) in patients in whom the pancreas graft was lost. Regression of atherosclerosis occurred in 38% of patients with a functioning pancreas graft compared with 0% of patients of whom the pancreas graft was lost (P = 0.035). CONCLUSIONS—Our study provides, for the first time, evidence that in patients who have undergone SPK, progression of coronary atherosclerosis in patients with a functioning pancreas graft is reduced compared with patients with pancreas graft failure. Our observation is an important part of the explanation for the observed improved mortality rates reported in type 1 diabetic patients with end-stage renal failure after SPK compared with KTA. In light of these findings described above, SPK must to be carefully considered for all diabetic transplant candidates.

SUMMARY Aim Maternally inherited diabetes and deafness (MIDD) associates with a mutation at position 3243 in mitochondrial DNA. Phenotypic expression of MIDD includes Type 1-like and Type 2-like diabetes. This study examined whether HLA-DQ phenotype and the degree of heteroplasmy in leucocyte and oral mucosa DNA influence clinical expression of the 3242 mutation. Methods In a group of 20 unrelated probands with MIDD, eight with Type 1-like diabetes, 12 with Type 2-like diabetes, HLA-DQ type and degree of heteroplasmy for the 3243 mutation were determined. HLA-DQA1/DQB1 phenotypes were categorized as predisposing, neutral or protective for autoimmune-mediated Type 1 diabetes. Results No differences were observed between Type 1 and Type 2-like MIDD groups with respect to the cumulative frequency of protective and predisposing HLA-DQ types. Predisposing HLA-DQ types are more prevalent in MIDD patients than in the control population (P

BACKGROUND Monitoring of insulin secretion and sensitivity after pancreas transplantation remains a practical problem. METHODS We introduced the simple structural model, continuous infusion of glucose with model assessment (CIGMA), to obtain insulin secretion and insulin sensitivity estimations after 35 successful simultaneous pancreas-kidney transplantations. Eighteen non-diabetic kidney transplant recipients were used as control group. RESULTS The baseline characteristics were equal between the two groups except for higher fasting insulin levels in the pancreas transplant group. After the 1-hr CIGMA glucose load, the pancreas transplant group reached a mean +/- SD blood glucose of 8.2+/-1.7 mmol/L compared with 7.3+/-1.0 mmol/L in the control group (P = 0.05). Concurrent stimulated insulin and C-peptide levels were 48+/-28 mU/L and 2.3+/-0.9 nmol/L in the pancreas transplant group compared with 36+/-21 mU/L and 2.9+/-1.1 nmol/L in the control group (P = 0.1 and P = 0.03, respectively). Both the CIGMA estimation for secretion as well as the CIGMA estimation for sensitivity were lower in pancreas transplant group (P = 0.003 and P = 0.01, respectively). Mean +/- SE coefficients of variation for the model estimations were 15+/-4% for secretion and 17+/-6% for sensitivity. CONCLUSIONS We conclude that CIGMA can be used clinically to evaluate carbohydrate metabolism in pancreas-kidney transplant recipients. These patients have a reduction in insulin secretory capacity and evidence of more insulin resistance than non-diabetic kidney transplant recipients.

Aims To examine a disputed association between the Lewis(a−b−) phenotype and Type 1 diabetes (T1D). Methods Lewis red blood cell phenotyping was performed for 97 T1D White patients and 100 control subjects using monoclonal antibodies. Two historical cohorts were also included as a control population. Results T1D patients had a lower frequency (4.1%) of Lewis(a−b−) blood group compared with simultaneously tested healthy control subjects (10.0%) and the historical control group (11.1%, P = 0.02). Male T1D patients showed a Lewis(a−b−) frequency of 8.0%, which was similar to both matched healthy male donors (9.8%) and historical (9.5%) male control subjects. Unexpectedly, none of the female T1D patients displayed Lewis(a−b−) phenotype, vs. 10.3% and 10.8% of female control subjects (P = 0.039 and 0.017). Conclusions The Lewis(a−b−) phenotype occurs less frequently in T1D compared with healthy control subjects with a strong female gender bias.

Several studies show an association of a guanine for adenine substitution (A-->G) at position 3243 in mitochondrial DNA (mtDNA) with a recently recognized diabetic subtype designated maternally inherited diabetes and deafness (MIDD). This mutation shows heterogeneity in its phenotypic expression as is apparent from its association with several other syndromes. Screening for the 3243A-->G mutation in mtDNA was performed in those diabetic patients attending the Leiden University Hospital diabetics clinic who had a history of maternally inherited diabetes, sensorineural hearing loss, or both. Four individuals from three unrelated families were identified who suffered from progressive nondiabetic kidney disease in association with diabetes mellitus and hearing loss. The mode of inheritance suggested maternal transmission. The combination of renal failure and hearing loss had been misdiagnosed as Alport syndrome in three of the four individuals. Therefore, in addition to these three families, another 63 unrelated patients with possible Alport syndrome were selected at random. DNA from peripheral blood and other tissues from members of the three families and from the 63 additional Alport syndrome patients was examined for the presence of the 3243A-->G mutation in mtDNA. The mutation was detected in heteroplasmic form in the four patients and their maternal relatives. Also, one of the 63 suspected Alport syndrome patients showed heteroplasmy for the 3243 mutation. These data show the existence of a kidney disease that is characterized by the presence of the A-->G mutation at position 3243 in the mtDNA.

Background. Although technical success rate of simultaneous pancreas kidney (SPK) transplantation in insulin-dependent diabetes mellitus (IDDM) patients with diabetic nephropathy has improved, morbidity remains high due to infection and rejection. The purpose of this study was to analyse infections encountered in our series of SPK transplants, using a restrictive antibiotic prophylaxis policy. Methods. We reviewed all infectious diseases after 66 consecutive bladder-drained SPK transplantations in 64 IDDM patients with end-stage renal disease due to diabetic nephropathy. During follow-up, the perioperative antibiotic regimen was altered (from 5 days pre-emptive therapy with multiple drugs to 1 day prophylaxis with cefamandole), and long-term viral prophylaxis (high-dose aciclovir) was introduced. For post-operative urinary tract or opportunistic infection, no prophylaxis was given. Results. Overall mean infection rate was 2.9 infections/ patient/year after a mean follow-up of 2.3 years. Surgical site infections (SSI) were seen in 30% of the patients, with Enterococci present in 47%. Logistic regression showed one day cefamandole prophylaxis to be associated with SSI, but there was no significant influence of SSI on either graft or patient survival. Forty-eight percent of all infections were lower urinary tract infections (UTI). There were 59 first UTIs (89%), probably related to long-term Foley catheter use, and 47 second UTIs (71%). Subsequent UTIs were not microbiologically related to first UTIs. Cytomegalovirus (10 patients) and other opportunistic agents did not cause mortality or graft loss. Five grafts were lost due to infection (SSI three times, post-transplant lymphoproliferative disease twice). Only one patient died because of infection (2%). Conclusions. Infectious diseases after SPK transplantation caused significant morbidity but did not influence either patient or graft survival. A change in prophylactic policy for both SSI as well as recurrent UTI, combined with earlier Foley removal, may lower incid-ences of these infections.

Diabetes mellitus is a common disease with variations in its clinical expression and different modes of pathogenesis. The purpose of this review is to discuss a recently identified diabetic subtype. Based on the triad diabetes, maternal inheritance and impaired hearing in this subtype we have proposed the name Maternally Inherited Diabetes and Deafness (MIDD). This diabetic subtype associates in the vast majority of cases with a single mutation in mitochondrial DNA, at position 3243. The clinical presentation of MIDD which can be IDDM-like or NIDDM-like, its frequency of occurrence, possible pathogenic mechanisms and the contribution of other mitochondrial DNA mutations to the development of diabetes will be discussed.

Recording site is an important cause of variability of compound muscle action potential (CMAP) and conduction parameters, which can be reduced by using large electrodes. Repeatability of CMAP and conduction parameters of conventional and large electrodes was compared in 16 controls and 17 diabetic neuropathic patients, using defined recording sites linked to anatomical landmarks. Right-sided median, peroneal, and tibial nerves were investigated twice by the same examiner, with a 1–2 week interval. Compared to previous studies, conventional electrodes on strictly defined recording sites resulted in better repeatability: intraindividual coefficients of variation (CV) varied between 4% and 14.4% for all parameters. CV of conduction parameters, not published previously, was smaller than CV of CMAP parameters. The use of large electrodes improved repeatability further: large electrodes resulted in substantially smaller CV for duration, amplitude, area, and changes of amplitude and area over a length of nerve, which were reduced by 10%, 31%, 29%, 27%, and 16%, respectively. Patients had higher CV than controls; large electrodes reduced patient CV more than control CV, resulting in less contrast between groups. Strictly defined recording sites and large electrodes improve repeatability of motor conduction studies to relevant degrees: all CMAP and conduction parameters are suitable for longitudinal studies of neuropathic patients. © 1996 John Wiley & Sons, Inc.

We showed previously that a mutation in the mitochondrial tRNALeu(UUR) gene at position 3243 associates with maternally inherited diabetes and deafness (MIDD). This mutation shows heteroplasmy in DNA from peripheral blood and other tissues. To examine whether heteroplasmy levels in peripheral blood DNA change upon aging, heteroplasmy levels were determined in DNA samples from peripheral blood, collected recently and 1.5-6 years ago, from 18 individuals carrying the 3243 mutation. It was found that 17 out of 18 carriers showed a decrease upon aging (P = 0.001), the average change being -0.69 +/- 0.61% per year. These data indicate a continuous selection against haematopoietic (precursor) cells carrying high levels of the 3243 mutation. Moreover, they imply that heteroplasmy levels may decrease below the detection limit if DNA from peripheral blood is analyzed from elderly individuals. DNA from oral mucosa cells was found to be a good alternative as heteroplasmy levels for the 3243 mutation are on the average 1.7 fold higher than in DNA from peripheral blood.

We have recently described a mitochondrial DNA (mtDNA) point mutation at np 3243 in the tRNA Leu(UUR) gene in a large Dutch pedigree with maternally inherited diabetes mellitus and deafness (MIDD) illustrating the importance of mitochondrial function in maintenance of a proper glucose homeostasis. In this review we will focus on the prevalence of the mtDNA mutation at np 3243 in diabetic populations, as well as postulate some working models for its pathogenicity. © 1995 John Wiley & Sons, Inc.

The relationship between fall in blood pressure (BP) on standing and supine BP before standing up was studied in 75 healthy controls and in 500 patients with diabetes mellitus (DM) using conventional BP measurements. The influences of physiological (sex, age, height) and DM-related factors (type, duration, HbA1c-level, use of insulin, oral antidiabetic and anti-hypertensive medication) on BP-fall were assessed. The effects of using a fixed abnormality threshold and a new supine BP-related abnormality definition on interpretation of the test were determined. Highly significant relationships of BP-fall with supine BP were found in control and DM subjects. Slopes did not differ between these groups. Slopes for systolic BP-fall were steeper in type 1 than in type 2 DM patients. A forward stepwise regression procedure revealed that supine BP (explaining 24% of variance) and HbAIc (explaining 1%) had significant influences on systolic BP-fall. Diastolic supine BP explained 14% of diastolic BP-fall, age 3%, and sex 2%. Only supine BP was thus of practical relevance in explaining BP-fall. Taking supine BP into consideration affected test results: of 74 subjects with an abnormal conventional systolic BP-fall, 10 (13.5%) had been misclassified according to the new method, and 4 additional patients had been misclassified as normal. Classification changes were much larger for diastolic BP-fall (63% of conventionally abnormal results were reclassified as normal), but the range of diastolic BP is smaller than for systolic BP, meaning that the measurement error interferes with its clinical utility. BP-fall was higher in type 2 than in type 1 diabetics, and higher in those using anti-hypertensives than in those who did not. These effects were due to differing supine BPs, showing that taking supine BP into account can prevent incorrect conclusions regarding abnormality of the standing up test in DM. The validity of this test can be improved by accounting for supine BP.

Pancreatic graft procurement, preservation, and transplantation surgery may result in damage to and loss of the integrity of endocrine cells and consequently in leakage of cell products into the insular vascular capillaries. Thus, the amount of alpha-, beta-, and pancreatic polypeptide (PP) cell products released into the vascular space of the recipient immediately after graft reperfusion may reflect islet cell injury. To test this hypothesis, we assessed glucagon, PP, C-peptide, and insulin levels in a prospective study of 22 consecutive renal-pancreatic transplantations. Transplantation-related parameters were used to account for differences in hormone release. Five grafts were preserved using Euro-Collins preservation fluid and 17 grafts were preserved using University of Wisconsin solution (UW). The first sign of a reinstalled physiological axis was the decrease of the blood glucose concentration after a median duration of 40 min (range 5-90 min) and the association of the recipient's ambient blood glucose levels with insulin release between 25 and 180 min after reperfusion. The delay period before a fall in blood glucose was observed correlated with cold ischemia time (rs = 0.73, P < 0.001, n = 21). An immediate and marked increase in plasma levels of glucagon (from 180 +/- 18 to 585 +/- 99 ng/L, mean +/- SEM), PP (from 57 +/- 8 to 122 +/- 13 pmol/L), C-peptide (from < 0.06 +/- 0.02 to 5.43 +/- 0.63 nmol/L), and insulin (from 0.15 +/- 0.21 to 2.05 +/- 0.26 nmol/L) was observed. C-peptide release correlated with glucagon (r = 0.76, P < 0.001) and PP (r = 0.60, P < 0.01). The hormone release was compared with computed tomography scans that were performed in the immediate postoperative period in 15 UW-preserved allografts. The diameter of the pancreatic head was increased and ranged from 4.5 to 7.7 cm (mean 6.2 cm). Peroperative C-peptide release significantly correlated with morphological graft changes reflected by the pancreatic head diameter (r = 0.58, P = 0.02). In a stepwise multiple regression analysis, cold ischemia time was a significant factor for the release of PP (r2 = 0.18, P = 0.049) and C-peptide (r2 = 0.35, P = 0.004). We suggest that peroperative hormone release reflects endocrine tissue damage. Furthermore, cold ischemia time may jeopardize the pancreatic allograft after relatively short preservation times, even when UW is used.

Tolrestat is an aldose reductase inhibitor that is undergoing extensive clinical investigation for the treatment of diabetic complications including polyneuropathy. As part of a larger European trial, we report here the results from a single clinical center on the efficacy of tolrestat in patients with confirmed diabetic neuropathy. The trial was conducted in two phases: a 6-month double-blind, placebo-controlled phase, and a 6-month open-label phase in which most patients were treated with tolrestat. Following the double-blind phase, motor and sensory nerve conduction velocity had significantly deteriorated in the placebo group, which did not occur during treatment with tolrestat. Deterioration of vibration threshold also occurred during placebo treatment and did not occur with tolrestat. During the open-label phase, motor nerve condition velocity and vibration threshold improved with tolrestat. Moreover, the deterioration of motor nerve conduction velocity and vibration threshold that had occurred in patients initially treated with placebo, was stopped during open-label treatment with tolrestat.

Pancreas and kidney transplantation (SPK) is the treatment of choice for patients with type 1 diabetes mellitus and end-stage renal failure. Gallstones are common after SPK transplantation but little is known about the true incidence and etiology of gallstones in this group. We therefore evaluated the incidence of gallstones and the presence of transplant-related risk factors in patients after SPK and kidney transplantation alone (KTA). Data were evaluated of 56 consecutive patients who underwent SPK transplantation and compared the results with those of 91 consecutive nondiabetic patients who underwent KTA transplantation at the Leiden University Medical Center between 1987 and 1994. Of the 58 evaluable KTA patients, 20.7% developed gallstones during 7.7 yr of follow-up and in the SPK group 43.9% of the 41 evaluable patients developed gallstones during 7.1 yr of follow-up. Postoperative weight loss and cyclosporin A-related hepatotoxicity correlated with gallstone formation both in SPK and KTA patients. In addition, the duration of postoperative fasting and autonomic neuropathy correlated with gallstones in SPK patients. It is concluded that both in patients after SPK transplantation and in patients after KTA transplantation, the risk to develop gallstones is significantly increased. Physicians should be aware of the high incidence of gallstones in SPK recipients.

Multiple pathogenic pathways are able to deregulate glucose homoeostasis leading to diabetes. The 3243A>G mutation in the mtDNA (mitochondrial DNA)-encoded tRNALeu,UUR gene was found by us to be associated with a particular diabetic subtype, designated MIDD (maternally inherited diabetes and deafness). This mutation causes an imbalance in the mitochondrion between proteins encoded by the nuclear and mitochondrial genomes, resulting in a gradual deterioration of glucose homoeostasis during life. Remarkably, carriers of the 3243A>G mutation are generally not obese. The mutation also results in enhanced radical production by mitochondria. We propose that this mutation leads to the development of diabetes due to an inappropriate storage of triacylglycerols within adipocytes. The result is a fatty acid-induced deterioration of pancreatic β-cell function. In combination with an enhanced radical production in the β-cell due to the mutation, this leads to an age-dependent, accelerated decline in insulin production. In common Type 2 (non-insulin-dependent) diabetes, which is generally associated with obesity, a decline in mitochondrial function in adipose cells seems to result in an inappropriate scavenging of fatty acids by β-oxidation. As a consequence, a systemic overload with fatty acids occurs, leading to an enhanced decline in β-cell function due to lipotoxicity.

The 3243A>G mutation in mitochondrial DNA (mtDNA) is a genetic variant that is associated with a high risk of developing diabetes during life. Enhanced aging of pancreatic beta-cells, a reduced capacity of these cells to synthesize large amounts of insulin,and a resetting of the ATP/ADP-regulated K-channel seem to be the pathogenic factors involved.

Summary Background In diabetes mellitus, both retinopathy and nephropathy represent specific microvascular disease with increased capillary permeability resulting in hard exudates, foveal oedema, and albuminuria. The decrease of heparan-sulphate content of the glomerula-basement membrance in quantitatively related to the rate of proteinuria in nephropathy associated with insulindependnet diabetes mellitus (IDDM). Several short-term studies in patient with IDDM and non-IDDM have shown that a reduction of microabluminuria and macro-albuminuria can be achieved with the supplementation of glycosaminoglycans. After completion of a study on the effect of danaparoid sodium on albumin excretion in patients with IDDM and macroalbuminuira, we hypothesised that treatment with danaparoid sodium also influenced retinal leakage in the patients in that trial. Methods In this retrospective study nine patients with nephropathy received 750 anti-Xa units danaparoid sodium once a day for 6 weeks in a placebo-controlled double-blind cross-over study. Funds photographs, done at baseline and at the end of the study, were semiquantitatively scored for the severity of hard exudates. Findings At baseline 14 eyes had grade 1 to 5 severity of hard exudates and four eyes were without hard exudates (grade 0). There was no progression in the latter four eyes. In ten eyes an improvement was observed: four patients showed a favourable response to treatment in both eyes and two patients showed improvement in one eye. We found improvement of hard exudates after 6 weeks of treatment with danapariod sodium. Interpretation Our uncontrolled observation indicates that the supplementation of danaparoid sodium influences both the permeability of retinal vessels as well as of glomeular vessels. Danapariod-sodium therapy as a systemic adjuvant is worth considering for treatment strategies for foveal oedema and hard exudates in diabetic maculopathy.

Long-term prognosis of patients with type-1 diabetes mellitus and end-stage renal failure appears to be better after kidney transplantation compared with dialysis. Controversy exists about the additional benefit of a simultaneously transplanted pancreatic graft. We studied the effect on mortality of simultaneous pancreas-kidney transplantation compared with kidney transplantation alone from regional differences in transplantation protocols.All 415 patients with type-1 diabetes (aged 18-52 years) who started renal-replacement therapy in the Netherlands between 1985 and 1996 were included in the analysis. Patients were allocated to a centre based on their place of residence at onset of renal failure. In the Leiden area, the primary intention to treat was with a simultaneous pancreas-kidney transplantation, whereas in the non-Leiden area, kidney transplantation alone was the predominant type of treatment. All patients were followed up to July, 1997. Analyses, mortality, and graft failure were by Cox proportional-hazard model adjusted for age and sex.Simultaneous pancreas-kidney transplantation was done in 41 (73%) of 56 transplanted patients in the Leiden area compared with 59 (37%) of 158 transplanted patients in the non-Leiden area (p0.001). The hazard ratio for mortality after the start of renal-replacement therapy was 0.53 (95% CI, 0.36-0.77, p0.001) in the Leiden area compared with the non-Leiden area. When just the transplanted patients were analysed the mortality ratio was 0.4 (95% CI 0.20-0.77, p=0.008) and was independent of duration of dialysis and early transplant-related deaths. Equal survival was found for patients on dialysis only.These data support the hypothesis that simultaneous pancreas-kidney transplantation prolongs survival in patients with diabetes and end-stage renal failure.

In diabetic nephropathy, heparan sulfate glycosaminoglycan side chains are reduced in glomerular basement membranes proportionally to the degree of proteinuria. Recently, it was demonstrated that additional therapy with danaparoid sodium, a mixture of sulfated glycosaminoglycans with mainly heparan sulfate, lowered proteinuria in type 1 diabetes patients with diabetic nephropathy. A randomized placebo-controlled parallel study was performed with 750 anti-Xa units of danaparoid sodium once daily in type 2 diabetes patients with severe proteinuria. The aim of the study was to evaluate the possible effects of danaparoid sodium on proteinuria, endothelial dysfunction, and hard exudates in the retina and to determine the safety/tolerability of this drug. Twenty-two patients completed the study, and one patient had to stop prematurely after 6 wk of danaparoid sodium treatment because of urticaria at the injection sites. Apart from a small decrease of hemoglobin and minor skin hematomas at the injection site in five patients in the danaparoid sodium group, no other safety parameters showed any clinically or statistically significant difference between and within groups. The relative change in time of both the urinary albumin and protein excretion rate corrected for creatinine did not differ between both treatment arms (P = 0.2 and 0.49, respectively). No retinal complications or changes of hard exudates occurred. von Willebrand factor was elevated in both groups, but was not influenced by either treatment modality. Contrary to the beneficial effects that occurred in type 1 diabetes patients with diabetic nephropathy, treatment for 8 wk with 750 anti-Xa units of danaparoid sodium gave no reduction of proteinuria, hard exudates, and von Willebrand factor.

In diabetic nephropathy, expression of glycosaminoglycan side chains of heparan sulphate proteoglycan in the glomerular basement membrane is reduced proportionally to the degree of proteinuria. We performed a cross-sectional study to evaluate whether non-vascular basement membranes also show a decrease in heparan sulphate side chain staining in patients with diabetic nephropathy. We evaluated the skin basement membrane for extracellular matrix components in the following groups: control subjects (n = 16); patients with Type 1 diabetes and normoalbuminuria (n = 17), microalbuminuria (n = 7), and macroalbuminuria (n = 16); patients with Type 1 diabetes and diabetic nephropathy undergoing renal replacement therapy (n = 13); and non-diabetic patients undergoing renal replacement therapy (n = 21). The following antibodies were used for this immunohistochemical study: monoclonal antibodies against the heparan sulphate side chain (JM403) and core protein (JM72) of the glomerular heparan sulphate proteoglycan; polyclonal antibodies against the core protein (B31); polyclonal antibodies against collagen types I, III, and IV, fibronectin, and laminin; and monoclonal antibodies against the noncollagenous domain of alpha1(collagen IV) and alpha3(collagen IV), against transforming growth factor beta(2G7), and against advanced glycosylation end products (4G9). Expression of heparan sulphate side chains was reduced in the skin basement membrane of patients with overt diabetic nephropathy, of those with Type 1 diabetes undergoing renal replacement therapy, and those with non-diabetic renal failure. Increased intensity of staining was found for collagen type I and advanced glycosylation end products in patients with diabetic nephropathy. Changes in the extracellular matrix of the skin basement membrane seem to be similar to those in the glomerular basement membrane. These findings support the suggestion that patients with diabetic nephropathy also have altered heparan sulphate and collagen staining in extrarenal basement membranes. However, patients with non-diabetic renal failure also had reduced expression of heparan sulphate in the skin basement membrane, suggesting that this finding is not specific for diabetic nephropathy.

Diabetic nephropathy is a progressive renal disease with thickening of the glomerular basement membrane and mesangial expansion and proliferation as histological hallmarks. The presence of the glycosaminoglycan side chains of heparan sulfate proteoglycan, an important constituent of the glomerular basement membrane, is decreased in diabetic nephropathy proportionally to the degree of proteinuria. Danaparoid sodium is a mixture of sulfated glycosaminoglycans consisting mainly of heparan sulfate. The study presented here involved performing a randomized placebo-controlled crossover study with danaparoid sodium in diabetic patients with overt proteinuria. The aim of the study was to evaluate the effect on proteinuria and safety/tolerability. Nine patients completed the study, without major side effects; the crossover study consisted of two 6-wk periods of treatment with 750 anti-Xa units danaparoid sodium subcutaneously once-daily or placebo. Following danaparoid sodium, significant declines of both albuminuria and proteinuria were found. After danaparoid sodium, the albumin excretion ratio standardized for urinary creatinine reduced with 17% in comparison with an increase of 23% after placebo (95% confidence interval of the difference,-75.9-3.9%; P = 0.03). The percentage change of the urinary protein excretion corrected for urinary creatinine differed at 8 wk significantly between both treatment arms (P = 0.001). Additional parameters for safety as hematological, hemostasis, biochemical parameters, and fundusphotography did not show any clinically significant difference for both groups. Only two patients had minor skin hematomas at the injection site while using danaparoid sodium. In conclusion, the supplementation was found to be feasible and was not associated with side effects. A significant decline of proteinuria was found. More prospective dose-finding and long-term studies must be performed to see whether danaparoid sodium could not only induce a reduction of proteinuria but also halt the progression of renal disease.

To examine the incidence of interstitial and vascular rejection in pancreas allografts and its impact on graft survival, we studied 36 percutaneous pancreas biopsies and 10 pancreas transplantectomy specimens from 32 patients who had undergone simultaneous pancreas-kidney transplantation. Interstitial rejection (IR) was predominantly found in the biopsies, while vascular rejection (VR) was most prominent in the transplantectomies. Pancreas graft survival was significantly decreased for pancreas grafts that had suffered from vascular rejection when compared to those with only interstitial rejection. Potential rejection markers, i. e., serum amylase, glucose, creatinine, and urinary amylase, did not correlate with histological signs of rejection, although increased levels of serum amylase were, in all but one case, associated with rejection.We conclude that a percutaneous pancreas biopsy remains the most reliable method to determine pancreas rejection, and that by distinguishing between IR andVR, a pancreas biopsy may provide important diagnostic as well as prognostic information.

Diabetes mellitus comprises a number of diseases with hyperglycemia as hallmark. Currently, multiple genetic factors are being recognized which contribute to the development of diabetes or which may modulate its clinical expression. This review presents an overview of our current knowledge on a diabetic subtype which associates with a single mutation in mitochondrial DNA. Based on the triad of Maternal Inheritance, Diabetes and Deafness we propose the name Maternally Inherited Diabetes and Deafness (MIDD) for this syndrome. In Northwestern Europe MIDD affects approximately 1.3% of all diabetic individuals.

The risk of cardiovascular morbidity and mortality is highly increased in patients with diabetic nephropathy. Postulating that the generalized vasculopathy observed in these patients may enhance transcapillary filtration of lipids and lipoproteins resulting in a more atherogenic interstitial lipid profile, we set out to analyze the composition of their interstitial fluid. We studied healthy control subjects (n = 9), normoalbuminuric insulin-dependent diabetes mellitus (IDDM) patients (n = 16), and IDDM patients with diabetic nephropathy (n = 11) matched for age, body mass index, smoking habits, duration of diabetes, and metabolic control. Interstitial fluid was collected after an overnight fast by applying mild suction (200 mmHg) to the skin. Interstitial apolipoprotein A-I (apoA-I) levels were significantly lower in patients with nephropathy (0.18 +/- 0.10 milligram [mean +/- SD]) compared with normoalbuminuric diabetic patients (0.29 +/- 0.08 milligram) and healthy control subjects (0.30 +/- 0.09 milligram). Interstitial apolipoprotein B:apoA-I ratios tended to be higher in patients with diabetic nephropathy. In these patients, normal interstitial low-density lipoprotein cholesterol concentrations were observed in the presence of lower apoA-I levels. Transcapillary filtration of apoA-I was significantly lower in patients with diabetic nephropathy. Furthermore, an altered multiple regression model explaining interstitial apoA-I levels was observed in diabetic nephropathy. In this model, transcapillary protein (IgG) filtration and serum apoA-I levels no longer explained interstitial apoA-I levels. If we assume that interstitial apoA-I is involved in reverse cholesterol transport, these data suggest a more atherogenic interstitial lipoprotein profile in IDDM patients with nephropathy.

Several groups have reported that recipients of a simultaneous pancreas-kidney transplantation suffer from more kidney rejection episodes than do recipients of a kidney transplantation (1-6). However, it is not known whether this is interstitial rejection, vascular rejection, or both. In this study, the renal biopsies and transplantectomies of 45 pancreas-kidney and 48 kidney transplant recipients were evaluated for the presence of interstitial and vascular rejection. Furthermore, the influence of OKT3 induction therapy on rejection after pancreas-kidney transplantation was studied. Of the 45 pancreas-kidney recipients. 4 patients did not suffer from rejection during follow-up, 28 suffered only from interstitial rejection, and 13 suffered from vascular (with or without interstitial) rejection, whereas 12, 19, and 14 of the 48 kidney transplant patients had no rejection, interstitial rejection, or vascular (with or without interstitial) rejection, respectively. Three patients with a kidney transplant were treated for rejection although no biopsy was taken. In the pancreas-kidney group, 38 of the total of 149 biopsies and transplantectomies taken contained no rejection, 92 had interstitial rejection, and 19 had vascular rejection. In the kidney group, these values were 13, 41, and 25, respectively, of 79 biopsies and transplantectomies taken (P = 0.002). Five-year renal graft survival was 79% in the kidney group and 60% in the pancreas-kidney group. Renal graft survival rates differed significantly (P = 0.02). Renal graft survival and occurrence of rejection did not reach significance between pancreas-kidney recipients treated with OKT3 induction therapy and pancreas-kidney recipients receiving conventional triple therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

The relative influence of diabetes mellitus-related and physiological factors on vibration perception thresholds was assessed in 353 patients in a hospital-based setting (173 insulin-dependent and 180 non-insulin dependent patients, aged 51.1 +/- 15.9 years) and 80 healthy controls (aged 43.3 +/- 15.2 years) employing a Biothesiometer. Vibration perception thresholds were bilaterally measured at the thumbs, medial malleoli and halluces. Sixty (17.0%) older patients had off-scale thresholds (> 50 V). As no systematic side differences were found, values of contralateral sites were averaged. Considering the effects of age, height, gender and skin temperature in controls, age accounted for 46.7 and 52.2% threshold variance at the ankles and halluces, respectively, while height explained 5.1 and 5.1%, respectively. At the thumbs, only age was of relevance. Age relationships with vibration thresholds in health did not differ from published reports at any site. In the patient group, influences of age, height, gender, skin temperature, years from diagnosis, HbAlc, serum creatinine, drop in systolic blood pressure on standing, and ankle/arm blood pressure indices were assessed for each type of diabetes. For both types, age and height again had relevant effects at the lower extremities as did age and gender at the thumbs. Skin temperature was only marginally significant at the halluces of NIDDM patients. Of the disease-related factors, HbAlc had the strongest effect: for both IDDM and NIDDM higher levels were associated with lower vibration sensitivity. Increasing disease duration led to significantly higher thresholds in IDDM patients.(ABSTRACT TRUNCATED AT 250 WORDS)

In a prospective study, 17 early baseline computed tomography (CT) scans were obtained 2 or 3 days after simultaneous kidney-pancreas transplantation. Morphological changes and their relevance to the early detection of graft rejection and complications were evaluated. The pancreatic grafts were enlarged and showed signs of mild pancreatitis. Serial scans obtained during the first renal graft rejection episode were compared with the baseline CT scans (n = 7). They showed a significant increase in pancreatic graft size in the case of biopsy-proven severe renal graft rejection (P = 0.008). Normally functioning pancreatic allografts showed a 15%-40% decrease in size 1-6 months after transplantation. We conclude that the morphological changes observed early after transplantation are compatible with mild pancreatitis, which may contribute to the development of pancreatic graft thrombosis. There is an increase in the number of morphological changes during severe rejection, yet enlarged pancreatic grafts appear to recover from transplantation-related damage and regain their normal size without signs of atrophy.

Non-insulin-dependent (type II) diabetes mellitus (NIDDM) is characterized by hyperglycaemia and insulin resistance, and affects nearly 5% of the general population. Inherited factors are important for its development, but the genes involved are unknown. We have identified a large pedigree in which NIDDM, in combination with a sensorineural hearing loss, is maternally inherited. The maternal inheritance and the observed decrease in mitochondrial enzyme activities of the respiratory chain indicate a genetic defect in the mitochondrial DNA. An A to G transition was identified at nucleotide 3,243, a conserved position in the mitochondrial gene for tRNA(Leu)(UUR). This mutation cosegregates with the disease in this family and is absent in controls, and indicates that a point mutation in mitochondrial DNA is a pathogenetic factor for NIDDM.

We have recently reported an A to G transition at nucleotide position 3243 in the mitochondrial DNA (mtDNA) tRNALeu(UUR)) gene in a large family with non-insulin-dependent diabetes mellitus (NIDDM). Characteristic was its maternal transmission and an associated sensorineural hearing loss. In a screening of a Dutch and French NIDDM population for the presence of the tRNALeu(UUR)) mutation we identified two new pedigrees in which NIDDM is present in combination with deafness. The mode of inheritance agrees with a maternal one. This result shows that patients with a phenotype of NIDDM and deafness can be identified within groups of NIDDM patients based on the tRNALeu(UUR)) mutation. The same mutation has also been linked to the syndrome of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). How the same mutation can give rise to different clinical phenotypes is not clear. We obtained the complete mtDNA sequence from our initial pedigree and identified a number of additional mutations that could confer the phenotype of the tRNA(Leu(UUR)) mutation to diabetes. We examined the presence of these additional, potentially pathogenic mutations in the mtDNA from the two new pedigrees and from a previously described British pedigree. The absence of these mutations in all three pedigrees shows that the tRNALeu(UUR)) mutation alone associates with the phenotype of NIDDM and deafness. We conclude that maternally inherited diabetes and deafness is a distinct subtype of diabetes that is associated with a single mitochondrial tRNALeu(UUR) mutation. We propose the abbreviation MIDD for this particular subtype.